Synthesis and biological evaluation of novel (<i>E</i>)-<i>N'</i>-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

Liang, Jing-wei; Li, Shilong; Wang, Shan; Li, Wan-Qiu; Meng, Fan‐hao

doi:10.1080/14756366.2019.1702655

Cited by 11 publications

(8 citation statements)

References 26 publications

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“…On the contrary, the combination of VEGFR-2 and c-Met inhibitors, like sunitinib and PF-04217903 remarkably lowers tumour invasion and metastasis. 18 Hence regarding drug resistance, multitarget TK inhibitors are more superior than single target inhibitors 19 .…”

Section: Introductionmentioning

confidence: 99%

“…Aza-heterocycle occupies adenine site in hinge region and forms from 0 to 3 HBs with highly conserved residues Met1160 and Cys919 in c-Met and VEGFR-2, respectively. Heterocycle ring can be surrogated by phenyl ring with HB groups like halogens and carboxamide ( Figure 2 ) 18 , 20 . Linker occupied the region adjacent to gatekeeper.…”

Section: Introductionmentioning

confidence: 99%

“…It has a little role in protein binding, but it is important to fix other pharmacophoric elements in the corresponding binding sites 8 . It may be (hetero)aromatic or aliphatic chain ( Figure 2 ) 6 , 7 , 18 , 20–22 .…”

Section: Introductionmentioning

confidence: 99%

“…For c-Met inhibition, HB domain acts as HBA by forming two HB by two carbonyl oxygen with Asp1222 and Lys1110 while for VEGFR-2 inhibition, HB domain acts as dual HBA/HBD by forming two HB by carbonyl oxygen and amidic NH with Asp1046 and Glu885 8 , 23 . HB domain can be dicarboxamide, 3-sulfonylacrylamide, (thio)urea, N -acyl(thio)urea, carbamoylmethyl carboxylate, N -acylhydrazone, and semicarbazone 3 , 18 , 22 , 24–27 . It also can be incorporated in nitrogenous five or six membered ring system with carboxamide substituent like pyrazole, imidazole, 1,2,3-triazole, pyridine, pyrimidine, pyridazine, quinoline, cinnoline, and naphthyridine 3 , 4 , 6 , 7 , 20 , 21 , 24 , 25 , 28–33 .…”

Section: Introductionmentioning

confidence: 99%

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Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

Hassan

Mubarak

Shehadi

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1 H ,3 H )-dione 2a – g , in addition to the preparation of some new derivatives namely, 3 and 4a – j . Three compounds namely, 2c , 4b , and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC 50 range 0.052–0.084 µM). Both compounds 4b , 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1 H ,3 H )-dione derivatives are promising antiproliferative candidates that require further optimisation. Highlights New 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives were synthesised and characterised. Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines. Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line. Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib. Compounds 4b and 4e showed remarkable c-Met inhibitory activity. Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis. In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib. Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to ca...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

Hassan

Mubarak

Shehadi

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Here we distinguish the binding sites of a series reported compounds by NDCG method, present the QSAR model at the ATP binding sites individually. In order to further test the model and develop the bifunctional agents, it served to screen a database of TKIs that we built earlier [21][22][23]. The hit compound and its derivatives were synthesized, with the purpose of achieving the ABCG2/TK dual-target inhibitors with anti-drug resistance activity.…”

Section: Introductionmentioning

confidence: 99%

Discovery of ABCG2/VEGFR2 Dual-Target Inhibitor With Anti-Drug Resistance Activity Based on the ATP Binding Site

Liang¹,

Dai²,

Li³

et al. 2020

Preprint

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Background: ABCG2 plays a critical role in multi-drug resistance in a variety of cancers. Its activity is influenced by ATP hydrolysis and substrate transport, which are synergistic processes but in two independent sites. However, there was no QSAR study of the ABCG2 inhibitors for the two binding sites respectively. Methods: in current study, a QSAR model of ATP binding site was built using DCG scoring strategy, it was used to optimize the structure of a tyrosine kinase inhibitor to avoid the potential drug resistance. Results: a series of novel dual target compounds with arylamide skeleton were obtained, which showed notable activity in enzyme activity test. Compound 7c and 7i showed significant inhibitory activity against drug-resistant cells. Conclusions: the QSAR of ATP binding site of ABCG2 was first discussed, the dual-target compound 7c proposed a new strategy to reverse drug resistance.

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Exploration of antiproliferative potential of modified triazole–benzohydrazone scaffold: Multitarget approach

Ali,

Khalaf,

Bhongade

et al. 2023

Archiv der Pharmazie

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A novel series of triazole–benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad‐spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME‐3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI‐38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR‐2), mesenchymal epithelial transition factor (c‐Met), proto‐oncogene B‐Raf, mitogen‐activated protein kinase kinase, extracellular signal‐regulated kinase, and phosphoinositide 3‐kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR‐2 and c‐Met with IC50 values of 0.055 and 0.042 μM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16‐ and 9.4‐fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug‐likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c‐Met and VEGFR‐2.

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Synthesis and biological evaluation of novel (E)-N'-benzylidene hydrazides as novel c-Met inhibitors through fragment based virtual screening

Cited by 11 publications

References 26 publications

Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

Design and biological evaluation of 3-substituted quinazoline-2,4(1 H ,3 H )-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors

Discovery of ABCG2/VEGFR2 Dual-Target Inhibitor With Anti-Drug Resistance Activity Based on the ATP Binding Site

Exploration of antiproliferative potential of modified triazole–benzohydrazone scaffold: Multitarget approach

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